RESUMEN
Popliteal artery aneurysms (PAAs) are the most common peripheral arterial aneurysms and develop almost exclusively (>90%) in men who have a history of tobacco abuse at an average age of 65 years. Most PAAs are caused by chronic inflammation secondary to atherosclerotic disease; other nondegenerative causes of PAAs include arterial trauma, infection, Behçet's disease, medial fibromuscular dysplasia, or popliteal artery entrapment. Few case reports have been published on idiopathic congenital PAAs. We report a case of a 26-year-old man who presented with progressive claudication and subsequent acute limb ischemia due to the thrombosis of a large idiopathic PAA. Our case demonstrates that the differential diagnosis of young adult or pediatric patients presenting with signs of acute limb ischemia or claudication should include a symptomatic PAA.
Asunto(s)
Aneurisma/complicaciones , Claudicación Intermitente/etiología , Isquemia/etiología , Enfermedad Arterial Periférica/etiología , Arteria Poplítea , Trombosis/etiología , Enfermedad Aguda , Adulto , Aneurisma/diagnóstico por imagen , Aneurisma/fisiopatología , Aneurisma/cirugía , Fasciotomía , Humanos , Claudicación Intermitente/diagnóstico por imagen , Claudicación Intermitente/fisiopatología , Claudicación Intermitente/cirugía , Isquemia/diagnóstico por imagen , Isquemia/fisiopatología , Isquemia/cirugía , Ligadura , Masculino , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/fisiopatología , Enfermedad Arterial Periférica/cirugía , Arteria Poplítea/diagnóstico por imagen , Arteria Poplítea/fisiopatología , Arteria Poplítea/cirugía , Vena Safena/trasplante , Trombosis/diagnóstico por imagen , Trombosis/fisiopatología , Trombosis/cirugía , Resultado del Tratamiento , Injerto VascularRESUMEN
BACKGROUND: The Vascular Study Group of New England (VSGNE) conducted a pilot study evaluating the feasibility of 30-day data collection in patients undergoing infrainguinal bypass (INFRA) which was subsequently expanded to include a limited number of additional sites within the Vascular Quality Initiative (VQI). The purpose of our study was to use these data to evaluate the incidence of 30-day readmission after infrainguinal bypass. A secondary goal of the study was to perform a critical appraisal of the data elements and definitions in the 30-day dataset. METHODS: All infrainguinal bypass procedures performed during the pilot study period (7/2008 and 4/2016) were identified and merged with a dataset containing the 30-day data. Incidence and types of readmission were assessed. The primary endpoint was 30-day readmission, defined as any hospital readmission within 30 days of index operation; unplanned 30-day readmission was the secondary endpoint. Covariates tested for association with the primary and secondary endpoints included patient demographics, comorbidities, procedural, and postoperative characteristics. Variables significant on univariate screen (P < 0.2) were evaluated with logistic regression to identify independent determinants. RESULTS: Of 9,847 infrainguinal bypass patients, 5,842 (59%) patients were identified with 30-day data, and 907 (16%) were readmitted within 30 days. Of readmissions, 675 (85%) were unplanned. Potentially modifiable independent determinants of any 30-day readmission included 30-day surgical site infection (SSI) (odds ratio [OR]: 10, 95% confidence interval [CI]: 8.2-12, P < 0.0001), postoperative acute kidney injury (OR: 1.7, 95% CI: 1.2-2.5, P = 0.002), and discharge anticoagulation (OR: 1.2, 95% CI: 1.04-1.5; P = 0.02). Predictors of unplanned 30-day readmission were very similar but identified in-hospital major amputation as an additional independent predictor (OR: 2.8, 95% CI: 1.6-4.9, P = 0.0002). CONCLUSIONS: This study demonstrates the interest in, and value of, 30-day data collection in VSGNE/VQI and documents the frequency of readmission after infrainguinal bypass. Readmission within 30 days is strongly associated with SSI, stressing the importance of efforts to decrease this complication. Given that many other predictors are unmodifiable, 30-day readmission is only appropriate as a quality metric if it is risk adjusted using large, real-world datasets such as VQI. Lessons learned from this analysis can be used to select optimal 30-day data elements.
Asunto(s)
Implantación de Prótesis Vascular/efectos adversos , Extremidad Inferior/irrigación sanguínea , Readmisión del Paciente , Enfermedad Arterial Periférica/cirugía , Vena Safena/trasplante , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/fisiopatología , Reoperación , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.
Asunto(s)
Factores de Crecimiento de Fibroblastos/fisiología , Neoplasias de la Próstata/patología , Receptores Androgénicos/fisiología , Transducción de Señal/fisiología , Antagonistas de Andrógenos/uso terapéutico , Animales , Diferenciación Celular , Línea Celular Tumoral , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Humanos , Proteína 1 Inhibidora de la Diferenciación/fisiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Metástasis de la Neoplasia , Neoplasias de la Próstata/tratamiento farmacológico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/fisiologíaRESUMEN
Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen-deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by using signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We used an in vitro high-throughput RNA interference (RNAi) screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss-of-function promotes androgen ligand-independent growth. We identified 40 genes where knockdown promoted proliferation of both LNCaP and VCaP prostate cancer cells in the absence of androgen. Of these, 14 were downregulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoenzyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in several tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We show that loss of PPP2R2C promotes androgen ligand depletion-resistant prostate cancer growth without altering AR expression or canonical AR-regulated gene expression. Furthermore, cell proliferation induced by PPP2R2C loss was not inhibited by the AR antagonist MDV3100, indicating that PPP2R2C loss may promote growth independently of known AR-mediated transcriptional programs. Immunohistochemical analysis of PPP2R2C protein levels in primary prostate tumors determined that low PPP2R2C expression significantly associated with an increased likelihood of cancer recurrence and cancer-specific mortality. These findings provide insights into mechanisms by which prostate cancers resist AR-pathway suppression and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/enzimología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Proteína Fosfatasa 2/metabolismo , Andrógenos/deficiencia , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Análisis Multivariante , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteína Fosfatasa 2/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Androgénicos/metabolismo , Recurrencia , Transducción de Señal , Resultado del Tratamiento , Familia-src Quinasas/metabolismoRESUMEN
PURPOSE OF REVIEW: The review highlights recently discovered mechanisms that sustain castration-resistant prostate cancer (CRPC) growth and describes advances in CRPC therapeutics. RECENT FINDINGS: Recent reports have shed new light on the molecular processes underlying CRPC survival during androgen deprivation therapy (ADT). This study summarizes recent findings and comments on their clinical relevance. Included in this review is a discussion on molecular mechanisms that regulate androgen receptor (AR) signaling in normal prostate epithelium and CRPC, biologically significant differences in the androgen-regulated transcriptional programs of androgen-dependent prostate cancer and CRPC, and recent discoveries involving de-novo androgen production and transport. We review the status and results of current clinical trials and finally, discuss the implications of evidence suggesting a declining importance of AR signaling in prostate cancers with PTEN loss. SUMMARY: Advances in the understanding of AR signaling in CRPC have identified novel drug targets and improved the rational design of targeted therapy, while illuminating a subset of prostate cancers that may progress to become completely independent of the AR signaling program.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Castración , Ensayos Clínicos Controlados como Asunto , Humanos , Masculino , Neoplasias Hormono-Dependientes/metabolismo , Fosfohidrolasa PTEN , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/biosíntesis , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Merkel cell polyomavirus (MCV or MCPyV) is a recently discovered human polyomavirus that is implicated in the pathogenesis of Merkel cell carcinoma (MCC). Although the transmission route for MCV is not yet known, other polyomaviruses, such as BKV, cause non-malignant pathology in the urinary tract. Like MCC, prostate cancer predominantly affects the elderly. Furthermore, prostate cancers and premalignant precursors exhibit chronic inflammation, which suggests a possible infectious involvement. We therefore examined whether MCV might participate in the pathogenesis of prostate cancer. OBJECTIVE: To determine the presence of MCV RNA in prostate cancer and surrounding stroma or normal prostate tissue. STUDY DESIGN: RNA was extracted from 28 patient-matched cancerous and 28 benign prostate epithelial samples, and six additional cancer-adjacent stromal samples. All tissues were laser-capture micro-dissected. DNA and RNA from a sequence-verified MCV-containing MCC tumor served as a positive control. Quantitative reverse-transcription PCR was used to assess the presence or absence of MCV T antigen transcript. RESULTS: No MCV T antigen was detected in prostate carcinomas, patient-matched benign samples, or tumor-adjacent stroma, with appropriate sensitivity of the assay demonstrated by an MCC tumor. CONCLUSIONS: MCV infection appears unlikely to be a significant factor in prostate carcinogenesis and there is no evidence of the prostate serving as a reservoir for MCV.